Department of Genetics, King Faisal Specialist Hospital and Research Centre, P. O. Box 3354, Riyadh, Saudi Arabia.
Saudi Diagnostics Laboratory, KFSHI, P. O. Box 6802, Riyadh, 12311, Saudi Arabia.
J Nephrol. 2021 Jun;34(3):893-900. doi: 10.1007/s40620-020-00795-0. Epub 2020 Jul 8.
Congenital anomalies of the kidney and urinary tract (CAKUT) are a group of abnormalities that affect structure of the kidneys or other structures of the urinary tract. The majority of CAKUT are asymptomatic and are diagnosed prenatally by ultrasound scanning or found incidentally in postnatal life. CAKUT varies in severity and may lead to life-threatening kidney failure and end-stage kidney disease. Renal agenesis, a severe form of CAKUT, is a congenital absence of one or both kidneys. Bilateral renal agenesis belongs to a group of prenatally lethal renal diseases and is often detected on fetal ultrasound scanning during the investigation of oligohydramnios. Approximately 40% of fetuses with bilateral renal agenesis are stillborn or die a few hours postnatally. Mutations in many renal development genes have been shown to be associated with renal agenesis.
Six consanguineous Saudi Arabian families were recruited to study the molecular genetic causes of recurrent miscarriages and lost fetuses due to oligohydramnios, renal agenesis and other congenital anomalies. Whole exome sequencing was employed to underlying detect genetic defects.
Novel loss of function variants were detected in FRAS1 and FREM2. In FRAS1, a homozygous splice site variant c.9780+2T>C was found in an affected fetus, segregating form each parent. In addition, in three other families both parents were heterozygous for a frameshift variant (c.8981dupT; p.His2995Profs3) and splice site variants (c.5217+1G>C and c.8098+2T>A), respectively. In FREM2, a homozygous nonsense variant (c.2303C>G; p.Ser768) was found in an affected fetus, segregating from both parents. In another family, both parents carried a FREM2 heterozygous frameshift variant (c.3969delC; p.Asn1323Lysfs*5).
We describe consanguineous families with clinical features of antenatal oligohydramnios and bilateral renal agenesis, in whom we have identified novel pathogenic variants in FRAS1 and FREM2. These finding highlights the association between mutations in FRAS1 and FREM2 and antenatal/perinatal death.
先天性肾和尿路异常（CAKUT）是一组影响肾脏结构或尿路其他结构的异常。大多数 CAKUT 是无症状的，通过超声扫描在产前诊断，或在产后生活中偶然发现。CAKUT 的严重程度不同，可能导致危及生命的肾衰竭和终末期肾病。肾发育不全，一种严重的 CAKUT，是单侧或双侧肾脏缺失。双侧肾发育不全属于一组产前致死性肾脏疾病，通常在羊水过少的胎儿超声检查中发现。大约 40%的双侧肾发育不全胎儿是死产或在产后数小时内死亡。许多肾脏发育基因的突变已被证明与肾发育不全有关。
招募了 6 个沙特阿拉伯的近亲家庭，以研究由于羊水过少、肾发育不全和其他先天性异常而导致复发性流产和丧失胎儿的分子遗传原因。全外显子组测序用于潜在检测遗传缺陷。
在 FRAS1 和 FREM2 中检测到新的功能丧失变异。在 FRAS1 中，在受影响的胎儿中发现了一个纯合剪接位点变异 c.9780+2T>C，从每个父母那里分离。此外，在另外 3 个家庭中，父母双方均为移码变异（c.8981dupT；p.His2995Profs3）和剪接位点变异（c.5217+1G>C 和 c.8098+2T>A）的杂合子。在 FREM2 中，在受影响的胎儿中发现了一个纯合无义变异 c.2303C>G；p.Ser768），从父母双方分离。在另一个家庭中，父母双方均携带 FREM2 杂合移码变异 c.3969delC；p.Asn1323Lysfs*5）。
我们描述了具有产前羊水过少和双侧肾发育不全临床特征的近亲家庭，在这些家庭中，我们在 FRAS1 和 FREM2 中发现了新的致病性变异。这些发现强调了 FRAS1 和 FREM2 突变与产前/围产期死亡之间的关联。
